Demonstration ofendo-cis-(2S,3R)-Bicyclo[2.2.1]hept-5-en-2,3- dicarbonyl Unit as a Reverse-Turn Scaffold and Nucleator of Two-Stranded Parallel β-Sheets:  Design, Synthesis, Crystal Structure, and Self-Assembling Properties of Norborneno Peptide Analogues

Abstract

endo-cis-(2S,3R)-Bicyclo[2.2.1]hept-5-en (norbornene) dicarbonyl unit with a built-in U-architecture has been demonstrated to be an excellent reverse-turn molecular scaffold. A large variety of endo-cis-(2S,3R)-norborneno bispeptides containing almost all of the coded amino acids were synthesized and examined for conformational preferences by 1H NMR, FT-IR, CD, and X-ray crystallographic studies. While FT-IR and 1H NMR variable-temperature studies ruled out the presence of any significant amount of intramolecular hydrogen bonding in simple bispeptides (3a − h) (except in Aib bispeptide), the CD studies were clearly in favor of a β-turn type structure. Single-crystal X-ray studies on Aib, Val and Leu containing norborneno bispeptides (3b−d) provided convincing proof for the presence of reverse-turn conformation. While the interstrand Cα−Cα‘ distances (5.2−5.7 Å) were well within the range of those for β-turn structures, no interstrand intramolecular hydrogen bonding was seen in Val and Leu bispeptides; the Aib bispeptide forms a seven-membered hydrogen-bonded ring, thus, showing that the norbornene (2S,3R)-dicarbonyl template assembles peptide chains in reverse-turn conformation by virtue of its built-in U-shaped architecture at these positions, and hydrogen bonding may not be necessary to stabilize the turn structure. The endo-cis-(2S,3R) orientation of bispeptide chains is essential for turn structure as shown by the crystal structure of trans-(2R, 3R) and trans-(2S,3S) derivative of Val bispeptide wherein the two peptide chains move away from each other with the Cα−Cα‘ distance increasing to 7.1−8.2 Å. The norbornene 5,6-double bond was hydrogenated to 5,6-dihydro derivative which showed almost the same CD spectrum as its olefinic analogue. Oxidative cleavage [Ru (VIII)] of the 5,6-double bond in norborneno bispeptides, as demonstrated with Leu bispeptide, afforded novel cyclopentanoid peptide analogues. The promise of norbornene unit as a template for nucleating the formation of two-stranded parallel β-sheets with minimum structural complexity is shown by the preparation of higher members of norborneno bispeptides with the general structure NBE(Pep)2 [NBE = endo-cis-(2S,3R)-bicyclo[2.2.1]hept-5-en (norbornene) dicarbonyl unit; Pep = peptide strand with two, three, or four (same or different) amino acid residues]. In 1H NMR, the high 3 J HN α values (7.0−9.3 Hz) observed for the amide protons (Table ) coupled with the presence of medium to strong intrastrand sequential ROE connectivities d α N( i , i +1) spanning the entire three- or four-residue sequence in the peptide strands of 9a − e and 10 and the exhibition of relatively low-temperature coefficients (dδ/dT = − 0.2 to −3.4 ppb/K) for amide protons in DMSO-d 6 solvent (Table ) clearly suggested that hydrogen-bonded β-sheet conformers dominate the population. FT-IR and CD studies provided further support for parallel β-sheet structures. A particularly unique feature of the norborneno bispeptides is their strong tendency to self-assemble in the solid sta...

Incorporation of Conformationally Constrained ?-Amino Acids into Peptides

“…This may explain why compound 18 adopts well defined conformations in solution, but compound 17 does so only in the solid state. Subsequent to our work, the synthesis and conformational analysis of a variety of norbornene containing peptide derivatives analogous to compounds 17 and 18 has been reported, and again the formation of i-turn conformations was observed [52].…”

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

“…70,71 It is noteworthy that some rationally designed external units might not form structures as expected. Ranganathan et al 72 and Jones et al 73 designed bicyclo[2.2.1]heptane derivatives as proline structure mimics to provide nucleating turn mimics, separately (Fig. 3e).…”

The Design, Synthesis and Conformation of Some Newβ-Hairpin Mimetics: Novel Reagents for Drug and Vaccine Discovery

“…A pioneering contribution was made by Feigel who introduced the phenoxathiin ring system 25,26 , as well as substituted biphenyls 27 , to stabilize b-structure in peptide loops ( Figure 3). Epindolidine derivatives 36 , 2,2'-functionalized diphenylacetylenes 37,38 , the bicyclo[2.2.1]hept-5-en-2,3-dicarbonyl unit 39 , and even simple alkenes 40 have also been evaluated as b-sheet nucleators. Dibenzofuran-and biphenyl-based templates have been studied by Kelly and coworkers as b-sheet nucleators [29][30][31] .…”